Photodynamic therapy (PDT) is a treatment regime that can better differentiate cancerous and normal tissue while minimizing or eliminating many of the side effects associated with conventional chemotherapy and radiation. PDT combines light and endogenous oxygen with a photosensitizer localized in or around the tumor. Irradiation of the sensitizer produces a cascade of biochemical events that kill cancer cells either directly or indirectly through the induction of vascular damage to blood vessels feeding the tumor or through induction of a host response. PDT has regulatory approval in the USA, Canada, The Netherlands, France, Germany, and Japan for cancers of the lung, digestive tract, and genitourinary tract using Photofrin® as a photosensitizer. PDT with Photofrin® is also being evaluated as a protocol for treating cancers of the head and neck region and for treating pancreatic cancer, as well as a possible therapy against Karposi's sarcoma, cancers of the brain, breast (both primary and metastatic), skin, and abdomen.
Photofrin® has been shown to be effective against a number of malignancies and has led to the acceptance of PDT in the clinic, but it is not the “ideal” photosensitizer. Photofrin® and most other porphyrin-related sensitizers have a weak absorbance in the red region of the spectrum (≧630 nm where penetration of light in tissue is optimal, FIG. 1). Photofrin® also induces long-lasting skin photosensitivity (2-3 months) due to retention of porphyrin moieties in cutaneous tissue.
Because Photofrin® is not a well-defined, single agent, it is difficult to modify chemically for investigation of structure/activity relationships. These limitations and the acceptance of PDT as a treatment protocol have stimulated research efforts toward the development of sensitizers for PDT that fit the definition of an ideal sensitizer as described below.
An ideal photosensitizer should have the following characteristics: (1) chemical purity and known composition, (2) toxicity only in the presence of light, (3) preferential retention in the target tissue, (4) rapid excretion following treatment, (5) low systemic toxicity, (6) high quantum yield for the photochemical process (high triplet yields, φT, and long triplet lifetimes, τT, to generate singlet oxygen and other reactive oxygen species), and (7) strong absorbance with a high extinction coefficient, ε, in the 630-800 nm range where tissue penetration of light is at a maximum while still being energetic enough to produce singlet oxygen.
Different disease states may place entirely different requirements on the chemical and biological properties of the “ideal” sensitizer.
Based on Photofrin®'s success and acceptance as a clinical procedure, the next generation of porphyrin-related photosensitizers are currently being developed and evaluated in clinical trials. 5-Aminolevulinic acid (ALA)-induced generation of protoporphyrin IX, an effective PDT sensitizer, has received FDA approval for treatment of actinic keratosis and is in clinical trials for other conditions. However, ALA treatment is not as universal as exogenously administered porphyrins because different tissues produce different amounts of protoporphyrin IX.
Tetra(m-hydroxyphenyl)chlorin (mTHPC) and tin etiopurpurin (SnET2) absorb more strongly in the red region of the spectrum (λmax 652 nm, ε=30,000 M−1 cm−1 for mTHPC; λmax 660 nm, ε=28,000 M−1 cm−1 for SnET2) than Photofrin®, but still show undesirable skin photosensitization (up to 6 weeks after administration). Modifications of mTHPC (the preparation of polyethylene glycol/mTHPC conjugates) give an increase in tumor selectivity in a rat-liver tumor model and in a rat ovarian tumor model.
A benzoporphyrin derivative also absorbs strongly in the red region of the spectrum (λmax 690 nm, ε=35,000 M−1 cm−), and shows limited skin photosensitivity (3-5 days), but is rapidly eliminated from all tissues including the tumor providing a narrow treatment window 0.5-2.5 h post-injection. However, the benzoporphyrin derivative (as Verteporfin®) has been approved for the treatment of age-related macular degeneration where the rapid clearance is desirable.
Other naturally occurring porphyrin-related molecules have also been evaluated as photosensitizers. The bacteriochlorins have absorption maxima (λ max) between 760 and 780 nm and have been studied as photosensitizers by several investigators, but are extremely sensitive to oxidation.
HPPH (the hexyl ether derivative of pyropheophorbide a) is currently in Phase I clinical trials for treating basal cell carcinoma and Barrett's esophagus and was developed following a structure-activity relationship (structure/activity relationship) study correlating lipophilicity with PDT efficacy in a series of pyropheophorbide a derivatives.
Texaphyrins are related to porphyrins in structure, but have five nitrogen atoms in the central core. Phase II clinical trials have just been completed with lutetium texaphyrin (Lu-Tex) as a photosensitizer for recurrent breast cancer and Phase I clinical trials are beginning using Lu-Tex for recurrent prostate cancer and cervical cancer. Lu-Tex has shown minimal skin photosensitivity due to rapid clearance, which leads to a fairly narrow treatment window 4-6 h post-injection. A major advantage to using Lu-Tex is its strong absorbance deeper in the red region of the spectrum (λmax 732 nm, ε=42,000 M−1 cm−1) where tissue penetration of light is greater.
Gadolinium texaphyrin, where lutetium is replaced with gadolinium in the central core, has been developed as a radiation sensitizer to enhance radiation therapy. While results with the texaphyrins are optimistic, some concerns exist over their specificity, as well as pain during treatment.
Phthalocyanines and naphthalocyanines absorb even more strongly in the red region of the spectrum (λmax 670-780 nm, ε≧100,000 M−1 cm−1) and are in the early stages of preclinical and clinical evaluation.
The later-generation photosensitizers are structurally similar to Photofrin® (all nitrogen heteroatoms in the core ring) and might be expected to have similar biological targets. The photodamage produced by PDT with porphyrin- and phthalocyanine-related materials appears to be from a combination of extracellular damage to vasculature and lymphatic structures and direct cell killing through both necrotic and apoptotic pathways with the mitochondria as an important target.
While current sensitizer research has provided several porphyrin-related photosensitizers with considerable promise, a single, “ideal” sensitizer has yet to emerge. With later-generation photosensitizers, it is very unlikely that a single photosensitizer will ever serve all the-diseases in oncology. Therefore, it is desirable to extend PDT into the treatment of other conditions and hence, the need to develop new photosensitizers with optimal properties for treating a given condition. The development of new photosensitizers with optimal properties for treating a given condition will depend upon an understanding of structure/activity relationships within the new class of photosensitizers and their applicability in general to other classes. PDT is a viable therapeutic approach not only for the treatment of cancer, but also for diverse other disease states including actinic keratosis, psoriasis, and age-related macular degeneration. PDT may also be clinically beneficial in other treatments such as blood purging, clot removal, and the removal of arterial plaque. The sensitizers for each of these applications may require quite different characteristics for optimal efficacy.